ReviewThe role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury
Section snippets
Myelin-associated inhibitors
Cajal was the first to propose that the central nervous system (CNS) environment limits axonal regeneration after injury, but only recently has CNS myelin been identified as a major factor contributing to regenerative failure. In 1988, the laboratory of Martin Schwab provided the first direct evidence that CNS myelin contains proteins that inhibit axonal growth. In their first study, 35 and 250 kDa protein fractions were isolated from CNS myelin and these were subsequently shown to inhibit
Cyclic AMP analogues
Because MAG, Nogo and OMgp signal through a common pathway, pharmacological inhibition of PKC, Rho and ROCK is a logical strategy to promote axonal regeneration. However, it is also possible to manipulate the neuron at the molecular level so that it no longer responds to myelin inhibitors. This approach is derived from the observation that MAG is initially permissive to neurite outgrowth and only becomes inhibitory beyond a specific developmental time point. When P1 DRG neurons are plated on
cAMP-mediated axonal regeneration in models of spinal cord injury
The therapeutic potential of cAMP was recently assessed in three independent studies of spinal cord injury, each using different injury models and methods of increasing cAMP. In two of these studies, cAMP elevation was accomplished by inhibiting PDE4 activity with rolipram. PDE4 is the major source of phosphodiesterase activity in the CNS (Iona et al., 1998), making it a logical target for therapeutic intervention, and rolipram is a specific PDE4 inhibitor (Krause and Kuhne, 1988). It also has
Future directions
Many promising treatments have resulted from the identification of cAMP as a modulator of axonal regeneration, but of all the agents that have been tested to date, rolipram has shown the greatest potential. Arguably the most significant finding of the study by Pearse and colleagues (2004) was that acute administration of rolipram alone significantly improved axonal integrity and functional outcome. The fact that a single agent could so dramatically impact functional recovery after spinal cord
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